The field of the present invention is the automatic collection of oral fluids for subsequent analytical testing. Oral fluids means liquid secretions of the salivary glands and cervicular fluid mixed with other particles found naturally in the mouth including bacteria, leukocytes, sloughed epithelial cells, and particles of food and dental plaque (Soderling, E. "Practical Aspects of Salivary Analyses," in Tenovuo, J. O. (ed.), Human Saliva: Clinical Chemistry and Microbiology, Vol. 1. Boca Raton, Fla.: CRC Press (1988), Ch. 1, p. 2). The terms oral fluids, whole saliva, and saliva are used synonymously in this document.
The collection of body fluids for diagnostic analysis has long been used in the medical, diagnostic, forensic, veterinary medical and other fields to test and monitor for the presence of specific molecules within the fluid. Results of such analyte testing can be used to diagnose medical conditions, and to measure the concentration of pharmaceutical and other drugs or toxic substances in a human or animal subject. Analyte test results can also be used to monitor appropriate levels of therapeutic agents, or for other purposes. A subject's oral fluids may be used to test for a wide variety of types of molecules whose concentration in saliva is related to the circulating concentration of those molecules or related metabolites of substances in the blood. (Malamud, D. Saliva as a diagnostic fluid. Br. Med. J., 305, 207-208 (1990); Mandel, I. D. The diagnostic uses of saliva. J. Oral Pathol. Med., 19, 119-125 (1990); Mandel, I. D. "Salivary Diagnosis: Promises, Promises," in Malamud, D. and Tabak, L. (eds.). Saliva as a Diagnostic Fluid, Vol. 694: Annals of the New York Academy of Sciences, New York: The New York Academy of Sciences (1993), pp. 1-8.)
Use of saliva as a medium for analysis is desirable since it can be obtained by noninvasive methods, unlike blood product collection methods involving trained medical personnel using venipuncture or finger-stick methods of collection. Oral fluid collection can also be done in public without requiring privacy booths, bathroom facilities, and careful subject monitoring to avoid adulteration, sample replacement, sample dilution and other problems associated with urine collections.
Previously described devices for collecting samples of oral fluids from a subject can be divided into three general categories. The first category includes devices that have an absorbent material for absorbing the oral fluid. These devices have as a common feature an absorbent material that is placed in the mouth of the subject to obtain the saliva. The absorbent material absorbs the oral fluid and is then removed from the mouth of the subject for subsequent extraction of the oral fluid from the absorbent material by any of various means.
The need for an absorbing material in these devices limits the range of substances that may be analyzed, since it has proven difficult to produce an absorptive material which will not irreversibly trap some types of analytes which may need to be analyzed. Liquid extractants have been incorporated to facilitate removal of some types of absorbed analytes. Use of these liquid extracting agents may produce additional problems of nonreproducibility and may unnecessarily dilute the sample making determination of small concentrations of some analytes in oral fluids unreliable. Added complexity involved in using these extracting agents makes the test less reliable. Extracting agents typically do not release all types of absorbed molecules equally well. Nonreversible trapping thus limits the accuracy, precision, and reliability of absorbent collection devices when semi-quantitative or quantitative analysis is necessary. (Anglebe, C., Experience with the Salivette.RTM. and some findings concerning its applicability for the determination of salivary components. J. Clin. Biochem., 27, 4, 247-248 (1989).)
A second category comprises devices wherein the oral fluid is obtained by osmotic absorption. For example, U.S. Pat. No. 4,817,632 to Schramm discloses an oral fluid collection device with a semi-permeable membrane enclosing chemicals that create an osmotic pressure for drawing the oral fluid from the mouth into the chamber of the semi-permeable membrane. The sample may be later retrieved from the chamber with a needle attached to a syringe. Use of these osmotic absorption saliva collection devices is limited to lab-based situations where trained personnel are available to process the previously collected saliva samples.
These devices typically interact to nonreversibly adsorb some types of analyte molecules that may need to be measured. Sample recovery complicates the procedure. Lengthy collection times of several minutes, dilution of the saliva sample with other chemicals, and non-reproducible mixing of fluid with the hypertonic substance within the chamber cause additional problems. Obtaining acceptable accuracy and precision in subsequent semi-quantitative and quantitative diagnostic measurements has proven to be difficult with oral fluid collection devices based on osmotic collection of the sample.
The third category includes devices wherein oral fluids are collected by aspiration. For example, U.S. Pat. No. 5,050,616 to Wolff et al. includes an attachable collecting tube, a buffering chamber centrally located within the interior of the sampling device, an attachable storage tube and a means for providing suction to the sampling device. The buffering chamber has a tapered interior surface that allows the fluid to flow down into the storage tube under the force of gravity in order to preclude fluid from entering the suction means and to reduce the quantity of foam and bubbles in the sample.
South African Patent No. 934404 to Weber and van Wyk uses vacuum aspiration to affix a transparent collection wand to mouth tissue surrounding a specific salivary gland while saliva is collected by aspiration from the chosen salivary gland. Two different vacuum levels are used to hold the wand in place with an annular ring while collecting saliva at a different level of vacuum from the central portion of the collection device. The device includes a pressure gauge to indicate the vacuum level within the collection vessel and an air vent connecting the saliva collection chamber with the outside atmosphere in order to provide for the continuous flow and collection of saliva. Although this device provides for collection from a particular salivary gland, it is unsuitable for collection of saliva and oral fluids from the whole mouth.
These aspiration devices require significant interaction between the device operator and the subject and require periodic observation to determine when an adequate sample of saliva appears to have been collected. They do not assure that air bubbles are removed from the sample, which may be a frothy sample containing air and liquid, and they may not be suitable for collection of whole saliva from all regions of the mouth. Collection of saliva from a single gland requires additional time and does not provide a sample that is representative of whole saliva and may not be reflective of serum concentrations of certain analytes. None of the known devices provides for retention of volatile components of the saliva, which may need to be subsequently analyzed. Nor does any of the known devices automatically determine when an adequate volume of saliva has been collected. Accordingly, drawbacks of these known devices limit their usefulness for collecting oral fluids satisfactory for rapid, sensitive, accurate and reliable quantitative and semi-quantitative testing for diagnostic or forensic analytes.
It is therefore an object of the invention to provide an improved method and device for automatically collecting oral fluids suitable for subsequent analysis.